The ability of cells to form defined shapes, and to dynamically regenerate their cytoskeletal and membrane structures following damage, is one of the current mysteries of cell biology. In addition to being a fundamental cell biological problem, understanding development and regeneration of cellular morphology would be a starting point towards developing a whole new approach to regenerative medicine, in which rather than attempting to replace damaged cells with stem cell derived substitutes, one would induce the damaged cells to regenerate in situ. Currently there is almost nothing known about how cells generate and regenerate morphology. To address this question, we turn to a classical model system - the giant ciliate Stentor. This remarkable cell is large enough to allow microsurgical manipulation and is able to regenerate severed parts in a few hours to restore a normal cell shape. We will sequence the Stentor genome and analyze the genetic programs that underlie regeneration, in order to ask whether regeneration is equivalent to a re-activation of normal morphogenesis or a distinct repair mechanism, determine whether there are definable genomic modules whose activation could drive regeneration at the level of a single cell, and explore the role of the cytoskeleton and intracellular transport in the regeneration response. PUBLIC HEALTH RELEVANCE: There is tremendous interest in regenerative medicine, i.e. approaches to restore human tissues and organs that have been damaged due to injury or disease. Most studies of regenerative medicine have focused on developing methods to use stem cells to replace damaged cells. We propose an alternative approach, which is to induce the injured cells to repair themselves. Towards this end, we will study a classical single-celled organism that has the ability to regenerate itself following damage.